More than 5 million people in the United States alone have advanced left ventricular dysfunction with an increased risk of dying suddenly and by current guidelines are candidates for implantable cardioverter defibrillators (ICDs). The overall hypothesis of this proposal is that interactions between structural (substrate) and functional (trigger) abnormalities, some of which are genetically-determined, can be used to identify patients with structural heart disease at high risk of SCD. The objectives of this proposal are two-fold: to enhance understanding of the biological mechanisms that predispose to SCD in humans, and to develop a practical biomarker panel to identify patients at risk. We exploit programmatic strengths in genetics, proteomics, electrophysiology, and epidemiology and will leverage an ongoing prospective cohort study (PRospective Observational Study of the ICD in SCD, PROSE-ICD) of patients with structural heart disease and reduced left ventricular ejection fraction undergo ICD implantation for primary prevention of SCD. The extensive phenotyping and genotyping of the PROSE- ICD cohort will allow us to explore pathways of electrophysiological remodeling, inflammation, ischemia and myocardial injury, and genetic contributors to SCD in patients with advanced structural heart disease. Stored electrograms in the ICD facilitate the accurate diagnosis of potentially lethal ventricular arrhythmias providing a specific surrogate for arrhythmic SCD. Patients with defibrillators will be followed prospectively and divided into groups who experience an appropriate ICD firing for rapid symptomatic ventricular tachycardia or ventricular fibrillation, and those who remain free of life-threatening ventricular arrhythmias for a period of three years after device implantation. The three-year window creates a practical endpoint that will allow comparisons between groups during the granting period but all patients will be followed indefinitely. We will employ a surrogate of SCD in this study that will be referred to as arrhythmic sudden death (ASD) defined as adjudicated firings for ventricular tachycardia (VT) or ventricular fibrillation (VF) and deaths due to ventricular arrhythmia not corrected by the ICD. The size and design of PROSE-ICD will facilitate novel studies of pathways of genetic predisposition to ASD, electrophysiological remodeling, inflammation, ischemia and myocardial injury in patients with advanced structural heart disease using full cohort and case-cohort analyses. Serial blood sampling and ECG recording will allow for evaluation of potential biomarkers over time in the same patient. This will facilitate exploratory evaluation of serial analysis of serum protein and ECG markers of risk of ASD. The detailed phenotyping and ready availability of biological samples from this cohort will permit biomarkers identified in the other populations to be tested in PROSE-ICD for association with SCD and it surrogates.